Abstract | OBJECTIVE: Platelet α2A-adrenergic receptors (ARs) mediate platelet aggregation in response to sympathetic stimulation. The 6.3-kb variant of α2A-AR gene is associated with increased epinephrine-induced platelet aggregation in healthy volunteers. The cytochrome P450 2C19*2 ( CYP2C19*2) loss-of-function allele influences P2Y12-mediated platelet inhibition and hence the rate of major adverse cardiovascular events. We assessed the influence of 6.3-kb α2A-AR gene variant on platelet aggregation and its interaction with CYP2C19*2 loss-of-function allele in patients with stable angina on aspirin and clopidogrel (dual antiplatelet therapy). APPROACH AND RESULTS: Aggregation to 5 increasing doses of epinephrine (from 0.156 to 10 μmol/L) was assessed in aggregation units by Multiplate Analyzer and platelet reactivity in P2Y12 reactivity units and % inhibition by VerifyNow P2Y12 assay before percutaneous revascularization. Gene polymorphisms were analyzed with TaqMan Drug Metabolism assay. Of 141 patients, aggregation was higher in 6.3-kb carriers (n=52) when compared with wild types (n=89) at all epinephrine doses (P<0.05) apart from 10 μmol/L (P=0.077). Percentage inhibition was lower (P=0.048) in 6.3-kb α2A-AR carriers. Percentage inhibition was lower (P=0.005) and P2Y12 reactivity units was higher (P=0.012) in CYP2C19*2 allele carriers. Higher P2Y12 reactivity units (P=0.037) and lower percentage inhibition (P=0.009) were observed in carriers of both 6.3-kb α2A-AR variant and CYP2C19*2 allele when compared with wild-type or with either mutation on its own. CONCLUSIONS: The 6.3-kb α2A-AR variant is associated with increased platelet reactivity to epinephrine and has an additive effect along with CYP2C19*2 loss-of-function allele on P2Y12-mediated platelet responses in patients with stable angina on dual antiplatelet therapy.
|
Authors | Aaron J Peace, Fabio Mangiacapra, Els Bailleul, Leen Delrue, Karen Dierickx, Micaela Conte, Etienne Puymirat, Anne Lies Fraeymans, Pieter Meeus, Jozef Bartunek, Massimo Volpe, Emanuele Barbato |
Journal | Arteriosclerosis, thrombosis, and vascular biology
(Arterioscler Thromb Vasc Biol)
Vol. 34
Issue 6
Pg. 1314-9
(Jun 2014)
ISSN: 1524-4636 [Electronic] United States |
PMID | 24723553
(Publication Type: Journal Article)
|
Copyright | © 2014 American Heart Association, Inc. |
Chemical References |
- P2RY12 protein, human
- Platelet Aggregation Inhibitors
- Receptors, Adrenergic, alpha-2
- Receptors, Purinergic P2Y12
- Aryl Hydrocarbon Hydroxylases
- CYP2C19 protein, human
- Cytochrome P-450 CYP2C19
- Epinephrine
|
Topics |
- Aged
- Aryl Hydrocarbon Hydroxylases
(genetics)
- Blood Platelets
(physiology)
- Coronary Artery Disease
(blood, genetics)
- Cytochrome P-450 CYP2C19
- Epinephrine
(pharmacology)
- Female
- Humans
- Male
- Middle Aged
- Platelet Aggregation
(drug effects)
- Platelet Aggregation Inhibitors
(therapeutic use)
- Polymorphism, Genetic
- Receptors, Adrenergic, alpha-2
(genetics)
- Receptors, Purinergic P2Y12
(physiology)
|